Besides age, many other factors are thought to influence the onset and progression of Alzheimer's disease (AD), including genetics, diet, stress, education level, physical activity, and other neurological disease. Here we seek to evaluate the effects of such co-morbidities on AD. This application proposes to utilize a systematic approach toward elucidating the effects of co-morbid conditions on AD neuropathology and cognitive phenotype in the 3xTg-AD mouse model. We propose to study three common co-morbid conditions that are clinically relevant, amenable to study in a lab setting, and for which we already have substantial preliminary data. AIM 1. Stress as a co-morbidity that influences AD pathology. Stress is a risk factor for AD We recently reported that stress-level glucocorticoids increase APP, BACE, and A[unreadable] levels as well as augmenting tau. Here we propose to evaluate the effects of physiologically-relevant stress paradigms on AD pathology and cognition in 3xTg-AD mice. AIM 2. Determine the impact of global ischemic stress on A[unreadable] and tau pathology. Here we will investigate the link between ischemic stress and the development of AD pathologies. Our preliminary data show that global ischemic insults have diverse temporal effects on both A[unreadable] and tau pathology. We propose to fully elucidate these effects and explore the underlying molecular mechanisms that occur during and after ischemia which impact pathology. We seek to identify novel therapeutic targets, as we have found that ischemia leads to the rapid clearance of somatodendritic tau via lysosomal degradation. By exploring the triggers and taubinding partners involved, we can uncover signaling pathways that lead to the clearance of somatodendritic tau. Ultimately, our preliminary data show, in agreement with clinical data and other studies, that ischemia leads to an increase in AD related pathologies. The implications of this study are significant as ischemia is a prevalent feature among the elderly population and it is critical to determine its effects on the AD phenotype. Aim 3: Synergistic interactions among A[unreadable], tau and a-synuclein. Up to 50% of AD cases exhibit a- synuclein immunoreactive Lewy Bodies in addition to plaques and tangles (Raghavan et al., 1993; Hamilton, 2000). This common co-morbidity promotes an aggressive disease course and accelerates cognitive decline (Hansen et al., 1990; Langlais et al., 1993). Our preliminary data indicate that introducing a mutant a- synuclein transgene, as a way to induce LB formation in the brains of an AD mouse model, exacerbates the neuropathological and cognitive phenotype. We are now poised to determine whether A[unreadable]-directed therapies, such as A[unreadable] immunotherapy, will be effective in rescuing the cognitive decline in mice that also harbor Lewy body pathology. This aim is significant as it represents one of the first attempts to determine if currently pursued strategies against AD will be effective in patients with other forms of A[unreadable] dementia (i.e., Lewy body variant).PUBLIC HELATH RELEVANCE: Alzheimer's disease (AD) is the common age-related neurodegenerative disorder, and at present there is no cure. Unfortunately, the aged population is not only susceptible to AD but they also frequently succumb to other ailments that can influence its progression and severity. These other disorders can be considered co-morbidities, and surprisingly, there has not been a systematic investigation into the effects of co-morbidities on the progression of AD in animal models. This proposal seeks to determine the impact that co-morbidities such as ischemia and stress play on the development of AD in the 3xTg-AD mouse model. [unreadable] [unreadable] [unreadable]